Recommendations for immunization of solid organ transplant (SOT) candidates and recipients

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Recommendations for immunization of solid organ transplant (SOT) candidates and recipients

February 2014

Présidente / Präsidentin:

Prof. Dr. med. C.-A. Siegrist

Centre de vaccinologie et d’immunologie Université de Genève

Rue Michel-Servet 1 1211 Genève 4

Tel. 022 379 57 78 Fax 022 379 58 01 E-mail : claire-anne.siegrist@medecine.unige.ch

Sekretariat EKIF / Secrétariat CFV:

Bundesamt für Gesundheit / Office fédérale de la santé publique Sektion Impfungen / Section vaccinations

Büro:

Schwarztorstrasse 96 3007 Bern

Tel. 031 323 87 06 Fax 031 323 87 95 E-mail: epi@bag.admin.ch

Postadresse:

Postfach 3003 Bern

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Authors

1st Author: Prof. Dr. med. Christoph Berger Federal Advisory Commission on Immunisation

Members: R. Anderau, Neuchâtel; G. Bachmann, St.Gallen; C. Berger, Zürich; P. Bovier, Lausanne; M. Bouvier Gallacchi, Melide; A.

Diana, Chêne-Bougerie; P. Diebold, Monthey; C. Hatz, Zürich; U. Heininger, Basel; P. Landry, Neuchâtel; D. Schorr, Liestal; C.-A. Siegrist, Genève; F. Spertini, Lausanne; S. Stronski Huwiler, Zürich. Secretariat: Federal Office of Public Health, Section Vaccination Programmes and Control Measures.

Recommendations endorsed by:

The Swiss Society for Infectious Diseases (www.sginf.ch), the Swiss Transplantation Society (www.swisstransplantationsociety.com) and Swisstransplant (www.swisstransplant.org).

Dateiname

logo_swt_positiv_CMYK.eps Datum . .

to contents

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Contents

Authors 2

1. Introduction 4

2. Prevention of vaccine-preventable diseases in the pre-transplant period 4

2.1 Evaluation of vaccine-induced immunity in the pre-transplant period 4

2.2 Immunizations in the pre-transplant period 5

Table 1: Evaluation of immunization status in the pre-transplant period 5 3. Prevention of vaccine-preventable diseases in the post-transplant period 6

Table 2: Correlate of immunity to be checked, reached and documented 6

3.1 Evaluation of vaccine-induced immunity in SOT recipients 7

3.2 Immunizations of SOT recipients 7

Table 3: Completion of immunizations in the pre-transplant period 7

4. Cocooning: Immunization of close contacts of SOT recipients 8

Table 4: Recommended accelerated vaccination schedule in the pre-transplant period 8 5. Recommendations for individual immunizations in the pre- or post-transplant periods 9

5.1 Basic and complementary immunizations 9

Table 5: Evaluation and completion of immunizations in SOT recipients 9

Table 6: Immunizations for cocooning 9

Immunizations for high risk subjects 10

References 13

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1. Introduction

Solid organ transplant (SOT) recipients are at increased risk for infectious complications due to their chronic disease and to the iatrogenic immunosuppressive therapy required to prevent rejection of the allograft [1]. With respect to vac- cine-preventable diseases (VPD) this risk includes:

• A higher attack rate and higher risks for severe and com- plicated illness, as documented e.g. for varicella [2, 3], measles [4, 5], influenza [6] and invasive pneumococcal disease (IPD) [7, 8];

• Higher risks of not having been optimally immunized, delays of routine vaccinations being frequently observed in patients with chronic organ diseases even before they become SOT candidates [9–11];

• Limited efficacy and duration of vaccine-induced protec- tion in patients with chronic organ failure [12–14] and due to post-transplant immunosuppressive treatments [15, 16], depending on both the type of organ transplant and the immunosuppressive regimen [17, 18] and affect- ing the induction of primary responses more than the boosting of pre-existing immunity [19].

Two main periods are characterized with respect to the rel- ative risks of VPD and vaccination recommendations: the pre- and the post-transplant period. During each of these periods, specific recommendations prevail:

• For the evaluation and the documentation of the immu- nization status

• For the immunization of the patient and his household.

These recommendations provide information on which vac- cinations are indicated, on how to review and complete the vaccination status of the potential SOT candidate before transplantation, and on how to best evaluate the need for and the administration of catch-up and booster vaccina- tions in SOT recipients. For inactivated vaccines in SOT re- cipients, when specific data and recommendations are not available, the recommendations of the Swiss Immunization Plan (SIP) should be followed [20].

Sources of information: These guidelines are based on re- cent systematic and expert reviews and guidelines pub- lished in North America and Europe [18, 21–27]. Wherever possible and relevant, original studies have also been cited.

Overall, there is only few data for evidence of protection by vaccination of SOT recipients. Immunogenicity data, if available in this population are often based on thresholds indicating protection in healthy individuals. These recom- mendations are made on the available specific data, the international guidelines for SOT patients. Given that the general recommendations for immunization in SOT pa- tients are heavily based on routine schedules, this guide- line draws on the SIP [20].

Off label use: Some of the recommendations for vaccina- tions provided here involve off label use, as no files includ- ing these patients have been submitted to the regulatory authorities. As such, limitations for reimbursement may apply and would have to be discussed with the patient. In addition, patient information leaflets accompanying vaccine preparations may contain general or specific precautions for the use of vaccines in immunocompromised or SOT pa- tients. It must be stressed that for inactivated vaccines the safety profile is excellent and there are no known concerns

substantiated by evidence that would prohibit their use in SOT patients pre- or post-transplant.

2. Prevention of vaccine-preventable diseases in the pre-transplant period

Transplant candidates frequently suffer from severe under- lying chronic disease with a predictable clinical course eventually progressing to end-stage organ disease. Despite the increased risk for some VPD due to organ insufficiency even at the pre-transplant stage (e.g. hepatitis A in chronic liver disease [28], invasive pneumococcal disease in ne- phrotic patients [29]), these patients are often vaccinated with delay, incompletely or not at all [9–11]. Thus, updating vaccination to schedule and rapid catch-up have the highest priority before transplantation (basic and complementary vaccinations and specific at risk vaccinations). In order to achieve this aim once a chronic disease process has been diagnosed, it is necessary to define which immunizations have been completed, which are lacking or incomplete and which catch-up schedule is needed before transplantation to achieve optimal protection against VPD. In many cases an accelerated schedule may have to be used [23, 24], if SOT is expected in the near future.

This may also apply for patients who develop acute organ failure resulting in a need for emergency SOT, although time may be short to achieve full immunizations. In these patients, documentation of antibody responses to vaccines and careful prioritization of immunizations may be neces- sary.

2.1 Evaluation of vaccine-induced immunity in the pre-transplant period

Evaluation and documentation of the immunization status and the estimate of protection against VPD is of para- mount importance as the incidence and the risk for severe or complicated VPD increases with progressing organ dis- ease eventually requiring SOT, and persists thereafter. This evaluation and documentation is the basis and a prerequi- site to define which vaccinations are to be completed, whenever possible before SOT, in order to achieve best possible protection of the SOT candidate and recipient. It relies on the documentation of immunizations received (immunization records) and on vaccine-induced immunity (serological analyses). The recommended approach is indi- cated in Table 1.

2.1.1 Vaccinations records:

Once a patient is identified as having an acute or chronic diseases likely to lead to SOT, it is necessary to periodically review and update documentation of immunizations (pref- erably including an electronic documentation which may be shared between carers, as for example on www.meine­

impfungen.ch). This documentation must be available and reviewed at first contact in the transplantation centre and should be considered compulsory for listing. Note that pre-transplant documentation of completed immunizations by a healthcare professional is the strongest indicator for protection against VPD at the time of transplantation and indispensable for the interpretation of specific vaccine anti- body titres. This documentation should include a documen-

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tation of disease history where relevant, for example for hepatitis B or varicella infections.

2.1.2 Immunity against VPD (serology):

Documentation of immunity against all VPD (Table 2) should be achieved before transplantation. Because it may not be possible to assume protective immune responses even from a complete vaccination history as in healthy persons, the documentation of the vaccination status in SOT recipi- ents as well as in SOT candidates with end-stage organ disease should be completed by the determination of spe- cific antibody titres.

Determination of antibody levels as a surrogate marker for protection may be helpful when:

• it is unclear whether there is immunity (after disease or by immunization) against particular VPD

• the need for a booster immunization (e.g. tetanus, hep- atitis B) must be assessed

• the response after completed primary or a booster im- munization needs to be evaluated

• it is desirable to assess the likely (long term) protection.

The correlation of antibody levels with protection is best when the level is measured 1–3 months after completion of a primary immunization series or a booster dose. Immu- nity from vaccines/infections that confer sustained protec- tion (e.g. measles, VZV) may be checked at all times.

Based on data from healthy persons, correlates of protec- tion have been established for tetanus, Haemophilus influ­

enzae type b, hepatitis B, measles, rubella and varicella antibodies (Table 2) and should be determined to define

which vaccinations are still needed. Antibodies to hepatitis A and yellow fever also indicate immunity. Based on these results a catch-up schedule can be designed, including re- quired booster doses.

In patients with end-stage organ disease, antibody levels should be determined again after immunization to docu- ment vaccine-induced immunity. Specific antibody levels against other VPD such as pertussis, mumps, HPV, menin- gococcal infection or influenza have either not been charac- terized, are not established, not available, not required to demonstrate protection or lack a correlate for protection.

2.2 Immunizations in the pre-transplant period Completion of basic and complementary immunizations for patients with a chronic organ disease likely to result in SOT is vital to ensure optimal protection against VPD. Every ef- fort should thus be made to ensure that transplant candi- dates, including their close contacts, are completely vacci- nated as early as possible and in any case prior to trans- plantation [21–26].

The need for individual catch-up vaccinations pre-transplant is the result of the evaluation of the vaccination record and of the determination of specific vaccine antibody levels.

Evaluation of the immunization records should lead to:

• catch-up basic vaccinations, including those against tet- anus, diphtheria, pertussis, polio (IPV), measles, mumps, rubella, as well as for children < 5 years of age also conjugated vaccines against Haemophilus influen­

zae type b, and against pneumococcal disease, and chil- dren < 5 years and adolescents 11–19 years of age against meningococcus serogroup C [20].

Table 1

Evaluation of immunization status in the pre-transplant period

Basic and complementary vaccines Vaccines for high risks patients DT/dT, Pa/pa, IPV, (Hib), HBV, HPV,

MMR, VZV, (PCV13, MenC) PCV13, influenza, HAV, MenACWY Chronic disease state Immunization records Review immunizations from vaccina-

tion records, define the catch-up needed for completion and keep updated documentation available.

Initiate catch-up vaccination program where necessary (Table 3 ).

According to underlying disease; plus seasonal influenza; HAV in patients with liver disease

Serological analyses Generally not recommended. Generally not recommended.

Progression to end-stage organ disease

Immunization records Review immunizations from vaccination records, define the catch-up needed for completion and keep updated documentation available. Initiate catch-up vaccina- tion program where necessary (Table 3 ).

Serological analyses Serological evaluation to document baseline and post-vaccination immunity and to guide further vaccinations (Table 2 ). This should be completed during the pre-transplant period and at the very latest at the first visit to the transplant centre, at listing.

SOT candidates Immunization records Collect immunization status at the first visit to the transplant centre, at the latest at listing (the earlier the better) and keep up to date documentation available throughout:

Serological analyses Serological evaluation to document baseline and post-vaccination immunity and to guide further vaccinations (Table 2 ). This should be completed during the pre-transplant period and at the very latest at the first visit to the transplant centre, at listing.

Abbreviations for vaccines: DT/dT, diphtheria tetanus; Pa/pa, acellullar pertussis; IPV, inactivated polio; HBV hepatitis B; HPV, human papilloma virus; MMR, measles mumps rubella; VZV, vari- cella; MenC, conjugated meningococcus C; PCV13, 13-valent pneumococcal conjugate vaccine; HA, hepatitis A; MenACWY, quadrivalent meningococcal conjugate vaccine.

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Table 2

Correlate of immunity to be checked, reached and documented

• identify and immunize patients not yet immune against varicella and hepatitis B (importance of ascertaining in- fection status) and trigger their immunization.

• identify females > 9 years of age not yet immunised against HPV. Vaccination of boys against HPV may be considered given the enhanced risks of cancer in immu- nosuppressed patients.

• administer or catchup vaccines recommended to high- risk patients (including vaccines against influenza, pneu- mococcal disease, hepatitis A, as well as varicella and hepatitis B (see above) and consider particular exposi- tion pre- and post-transplant (TBE, rabies, yellow fever etc.).

Any missing vaccinations identified before transplantation should be administered as soon as possible, as indicated in Table 3.

Table 4 shows the recommended accelerated schedule for vaccination of SOT candidates based on international rec- ommendations and the SIP [20, 23, 24]. This schedule gives the minimal age for each particular vaccine and the scheme with the shortest possible immunization series.

Vaccine Indication for determination of specific antibody titres Specific antibody (IgG) and unit

Interpretation of serological analyses

During end-stage organ disease

At pre- transplant (listing)

After catch-up immunization (pre- or post-trans- plant)

Post trans-

plant Suscepti-

ble Some

protection Long term protection

Tetanus Yes, if history unclear (§)

If unknown

serology Yes At 12

months Anti-tetanus

toxoid (IU/l) < 100 ≥ 100 ≥ 1000

Haemophilus influenzae type b

Yes (children

< 5 years )(§) Yes, (If unknown serology in children

< 5 years)

Yes (children

< 5 years) At 12

months Anti-PRP

IgG (mg/l) < 0.15 ≥ 0.15 ≥ 1

Hepatitis B Yes (#, &) Yes, if unknown serology

Yes (#) Every 12

months (¥) Anti-HBs

IgG (IU/l) < 10 ≥ 10

(¥) ≥ 100

(¥)

Measles Yes Yes, if

unknown serology

Yes At 12

months Measles IgG, by EIA (IU/l) < 50

(*) 50-149

(*) ≥ 150

(**)

Rubella Yes Yes, if

unknown serology

Yes Not if

immune before SOT

Rubella IgG

(IU/ml) < 10 ≥ 10

Varicella Yes Yes, if

unknown serology

Yes At 12

months VZV IgG or

VZV-gp (IU/l) < 50

(*) 50–149

(*) ≥ 150

(*, **)

§ If history unclear, check antibody titre 4 weeks after a booster dose to define whether further doses are needed.

# Check anti-HBs IgG titre if last dose given < 5 years ago, or 4–12 weeks after completion of primary series or a booster dose;

& Include HBsAg and anti-HBc to exclude current/past infection.

¥ In immunosuppressed SOT patients, the unknown contribution of immune memory requires regular booster doses to maintain anti-HBs titers ≥ 10 IU/l at all time in patients at risk of exposure.

* Measles and VZV IgG, by commercially used tests; if positive= immune, if negative or doubtful: send serum for analysis by a more sensitive test [30] to the Laboratoire de Vaccinologie des Hôpitaux Universitaires de Genève.

** Loss of pre-existing immunity to measles / VZV may occur in SOT patients.

Live vaccines (MMR, VZV, YF) should no longer be adminis- tered after the patient is included on an emergency trans- plantation list and SOT is considered as likely within 4 weeks.

Specific antibody levels have to be checked after specific vaccination, as described above in Table 2. If protective lev- els are not reached, additional immunizations and serologi- cal controls are recommended.

Additional information on immunizations during the pre-transplant period is included in section 5.

3. Prevention of vaccine-preventable dis- eases in the post-transplant period

Impaired immune response under continued immunosup- pression in SOT recipients is associated with an increased incidence and risk for more severe and complicated VPD through:

• Waning (and/or delayed and partial recovery) of pre-trans- plant immunity [32].

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Table 3

Completion of immunizations in the pre-transplant period Vaccine

immunogenicity Basic and complementary

vaccines Vaccines for high risks

patients Documentation of

immunizations DT/dT, Pa/pa, IPV, (Hib), HBV,

HPV, MMR, VZV, (PCV13, MenC) PCV13, influenza, HAV, MenACWY

Chronic disease state Normal or already reduced (but better than later!)

To update according to SIP [37] + include VZV and HBV vaccines already during child-hood, consider HPV for boys.

Yearly seasonal in- fluenza; HAV immuniza- tion if liver disease (*).

Documentation of immunization status in immunization record.

Progression to end-stage organ disease

Normal or already reduced (but better than later!)

To update according to SIP and to serological analyses.

Use accelerated immunization schedule if needed.

Yearly seasonal in- fluenza;

HAV immunization if liver disease (*); PCV13 if severe disease;

PCV13 + MenACWY if splenic dysfunction

Documentation of immunization status and of serologies (+/–) in immunization record.

SOT candidates Normal or already reduced (but better than later!)

To update according to SIP and to serological analyses.

+ Use accelerated immunization schedule if needed.

+ No live vaccine if included on emergency transplantationlist.

– Yearly seasonal influenza;

HAV immunization if liver disease (*).

+ PCV13 immunization at time of listing.

+ MenACWY if splenic dysfunction

Documentation of immunization status and serologies (+/–) in immunization record and in the referral letter to the transplant centre.

Household contacts Normal To update according to SIP [37]

+ Including VZV vaccines already during childhood.

Yearly seasonal influenza

immunization. Documentation of immunization status in immunization record and in the referral letter to the transplant centre.

(*) Consider exposition / travel vaccines as TBE (FSME), rabies, Hepatitis A, Yellow Fever, meningococcal infections, etc. according to exposition risks before and after transplant. Special consideration should be given to yellow fever immunization which will remain contraindicated after SOT.

• Exposure to VPD through non-immune close contacts [23].

3.1 Evaluation of vaccine-induced immunity in SOT recipients

Evaluation and documentation of the immunization status and the estimate of protection against VPD is of paramount importance as the incidence and the risk for severe or com- plicated VPD increases with progressing organ disease eventually requiring SOT, and persists thereafter. This eval- uation and documentation is the basis and a prerequisite to define which vaccinations are to be completed to achieve the best possible protection of the SOT recipient.

The approach to evaluation of immunization status in post-transplant patients is outlined in Table 5. Please refer to Table 2 for correlates of immunity to be reached and doc- umented.

3.2 Immunizations of SOT recipients

Immunization post-transplant is necessarily limited by im- munosuppression, and live vaccine in general must not be used (varicella see below). In addition, vaccine responses under transplant-associated immunosuppression are im- paired to a greater extent than during the chronic disease pre-transplant stage. Nevertheless, inactivated vaccines provide some protection [18] and these should be used whenever necessary despite their limitations.

The following principles have to be considered:

• The ability to mount and/or maintain an appropriate im- mune response to immunizations is impaired by immu- nosuppression. This affects primary vaccination series more than boosters.

• There is no evidence to associate solid organ rejection episodes to vaccination, even with live or adjuvanted vaccines [21], [30, 33–38]. In contrast, there is an asso- ciation between infection including VPD as e.g. influ- enza and rejection episodes [39, 40]. In paediatric SOT recipients, infections exceed rejection episodes as a reason for acute hospitalisation [41].

• Live vaccines are in general contraindicated or to be used with extreme caution in SOT patients [42]. The ad- ministration of such vaccines to close contacts, how- ever, may provide relevant protection [43]. Special con- siderations apply to varicella immunization (see below).

• To maximize vaccine efficacy, post-transplant immuniza- tions should not be undertaken during the phase of maximum immunosuppression [44]. Some agents, such as mycophenolate mofetil, seem to have a strong nega- tive effect on the ability to mount antibody responses to vaccination [45, 46]. Similarly, it is not recommended to immunize during an episode of rejection requiring inten- sification of immunosuppression.

• The decision when to start immunization post-transplant has to balance the higher risks of exposure and suscep- tibility for VPD early after SOT and the lower immune

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Table 4

Recommended accelerated vaccination schedule in the pre-transplant period

Vaccine Minimum age # doses Schedule

(minimal interval in months) DTPa, IPV 6 weeks (> 7 years dTp a) first dose < age 1 year: 4 doses

≥ 1 year: 3 doses 0, 1, 2, + 1x ≥ 12 months 1, 2 0, 1, 6 1, 2

dT(pa) booster 8 years 1 dose every 10 years

Hib 6 weeks first dose < 1 year: 4 doses

12–59 months: 2 doses 0, 1, 2, + 1x ≥ 12 months 1 0, 2

Hepatitis B Birth 3

(hexavalent vaccines or rapid schedule: 4 doses; 11–15 years:

2 adult doses)

0, 1, 4

(1–3 primary doses + booster after ≥ 4 months)

Hepatitis A 6 months (off label < 1 years) 2 0, 4

PCV13 6 weeks

(off label > 5 years) first dose < 1 year: 3–4 doses 1 year: 2 doses

> 1 year: 1 dose

0, 1, 2 + 1x ≥ 12 months 1

Influenza 6 months children < 9 years:

2 doses in first season if 2 doses: 4 weeks interval.

MMR 6 months 2 doses 0,1 3, 4

Varicella 6 months 2 doses 0,1 3, 4

HPV (women) 9 years 2 doses if first dose < 15 years;

3 doses if first dose ≥ 15 years 0, (1), 4 MenACWY conjugate5 1 year (off label < 11 years) 2 doses (+ booster to be

considered every 5 years) 0, 2

1 3 doses in the first year of life: 4. dose a) > 6 months after dose 3 and b) after 12 months of age.

2 further DTPa-IPV at age 4 (–7) years, see SIP

3 not recommended if emergency listing with likelihood of SOT within 4 weeks (live attenuated vaccine)

4 if first dose < 12 months of age, give 2nd dose after 12 months of age or include a 3rd dose after 12 months of age.

5 prefer MenACWY conjugate vaccine to polysaccharide vaccine [31]

competence under intense iatrogenic immunosuppres- sion during the first months after SOT. Thus, at present it is recommended to wait for 6 to 12 months after SOT before revaccination (with inactivated vaccines) [23]. A notable exception is immunization against seasonal influ- enza, which may be recommended at all times after transplant to hopefully elicit at least partial immunity.

• Waning immunity has been recognized in previously im- munized SOT recipients with positive antibody titres be- fore and lower/undetectable titres after transplantation [24]. Breakthrough disease and liver rejection has also been documented in a previously immunized liver trans- plant recipient [47]. Factors such as the administration of a single instead of two vaccine doses, the type of immunosuppression (use of mycophenolate mofetil) or the failure to maintain an immunologic memory all may contribute to the observed waning of immunity [17, 24, 32, 48–51]. Despite waning immunity, immunization be- fore transplant generates immune memory which can often be successfully boosted post-transplant.

Thus, pre- and post-transplant immunizations are important and likely to provide the best possible protection against VPD.

Table 5 indicates how to evaluate, elicit or update vac- cine-induced protection in SOT recipients. Note that it is essential for every period :

1. to review immunization records to identify missing im- munizations.

2. to document immunization status in the immunization record.

When vaccinations are administered post-transplant (Table 5), a normal immune response cannot be assumed. As op- posed to routine immunizations in otherwise healthy indi- viduals, it is therefore recommended to assess specific vaccine antibody responses to as surrogate markers for protection (Table 2) and to define if additional doses should be recommended.

4. Cocooning: Immunization of close contacts of SOT recipients

Close contact persons of SOT patients are the family mem- bers (persons living in the same household) as well as the health care personnel taking care of SOT recipients. The im- munization status of all close contacts should be reviewed along the schedule suggested in the SIP and missing vacci- nations should be completed as soon as possible. Due to the high risk of the following VPD for SOT recipients and the po- tentially incomplete protection of SOT recipients, the immu- nity of close contacts against these VPD should be checked and or induced by vaccination. Close contacts should be eval- uated for immunity by history (e.g. varicella) and if immunity is unknown or the person is not immune, the following vacci- nations are recommended (evidence II-2) [23]:

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Table 5

Evaluation and completion of immunizations in SOT recipients

Table 6

Immunizations for cocooning Evaluation (see also pre-trans- plant evaluation)

Immune competence and vaccine res- ponses

Basic and complementary

vaccines Vaccines for high risks patients

DT/dT, Pa/pa, IPV, (Hib), HBV, HPV, MMR, VZV (PCV13, MenC)

PCV13, influenza, HAV, MenACWY

6 months after SOT Immunization record:

review and identify missing vaccinations, including 1x PCV13 before SOT.

Serological analyses:

none

Markedly reduced Generally not recommended Yearly seasonal in- fluenza; PCV13 if not received at listing

12 months after SOT Immunization record:

to review Reduced (proportional to immunosuppres- sion regimen)

To update according to

serological analyses. Yearly seasonal influenza Serological analyses:

Tetanus, (Hib), HBV, measles, VZV

No live vaccine PCV13 booster dose for all SOT recipients

Follow-up post-trans-

plant period Immunization record:

to review Serological analyses as needed based on individual history, immunosup- pression and risks of waning of vaccine- induced immunity (VZV, measles, HBV, S. pneumoniae

Catchup + update of inactivated vaccines (varicella see below) according to SIP [37] and serological analyses.

Yearly seasonal influenza immunization

Household contacts Immunization record:

to review Normal To update according to SIP

[37] including VZV vaccines already during childhood

Yearly seasonal influenza immunization

Vaccine Indication Dose

Influenza All Yearly

Varicella If negative history: serology*

if negative serology: immunize 2 doses

(interval > 4 weeks)

MMR If 2 doses are not documented: immunize 2 doses

(interval > 4 weeks) Hepatitis B All close contacts

if not yet immunized 3 doses (0,1,6 months)

* not needed in young children with negative history

As a general principle, non-live vaccines should be pre- ferred to live vaccines for close contacts of immunosup- pressed patients if available (for example inactivated IPV and influenza vaccines instead of live oral polio or nasal in- fluenza vaccines). However, there is no identified risk of transmission of MMR and minimal risk of transmission of VZV vaccines from close contacts [43]. The protection of the SOT recipient from transmission of wild type virus thus largely outweighs the only theoretical risks associated with the use of live attenuated vaccines for close contacts.

5. Recommendations for individual im- munizations in the pre- or post-trans- plant periods

This section provides the baseline evidence on which the current recommendations are based.

5.1 Basic and complementary immunizations dTpa (IPV)

There are no data on the incidence or severity of tetanus, diphtheria, or pertussis in transplant recipients. Vaccination with DTPa/dT is safe and immunogenic in paediatric popu- lations with end-stage renal and/or end-stage liver disease and immunogenic in paediatric SOT recipients [18, 52, 53].

Antibody responses are reduced and antibodies are lost at a more rapid rate in SOT recipients compared with healthy controls [18, 52, 54]. In accordance with the SIP, DT/dT(Pa/ pa) and IPV should be administered to SOT candidates as

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detailed in the general schedule. DT/dTPa/pa as inactivated vaccine can be given to post-transplant patients [21–23].

Although limited, there is some evidence that this inacti- vated vaccine is efficacious in SOT recipients [18, 19].

Haemophilus influenzae type b (Hib)

Immunization against Haemophilus influenzae type b should be considered according to recommendations for the vaccination of less than 5-year-old children in the SIP. It is not recommended in children older than 5 years and in adult SOT candidates and recipients. In children with end- stage organ disease it is recommended that antibody titres should be checked and a booster dose given if the titre is below the threshold (Table 2). Hib immunization post-trans- plant is expected to be less imunogenic than before. Nev- ertheless it is recommended in children < 5 years of age requiring catch-up, as it is reported to be effective in well-functioning paediatric renal allograft recipients [55].

MMR

In the pre-transplant period, two doses of MMR vaccine at least one month apart are recommended. The first MMR dose is usually recommended at the age of 12 months, but can be performed at the age of 6 months if required [20]. It is crucial to give two doses up to one month before trans- plantation, as this vaccine is contraindicated thereafter. If earlier vaccination is not documented, the adult transplant candidate (born after 1963) should be considered non-im- mune and receive two doses of MMR before transplanta- tion. In cases of doubt, serological evaluation may help confirm immunity (Table 2).

Currently, there is insufficient data to generate evi- dence-based guidelines for the use of MMR in transplant recipients under immunosuppression. Preliminary data on efficacy and safety suggest that the use of MMR in paedi- atric SOT recipients could be a reasonable strategy [42, 56, 57] and one study is currently ongoing in Switzerland with liver transplant children (Posfay-Barbe, K, personal commu- nication). Indeed, additional evidence is needed before this can be widely recommended. Meanwhile the importance of pre-transplant immunization of SOT candidates and close contacts cannot be overemphasized.

Hepatitis B

SOT recipients may have more severe and more rapidly progressive hepatitis B (HBV) infection and may also reacti- vate latent disease while under immunosuppression [28, 58, 59]. HBV vaccination may provide protection against donor derived infection, particularly important in settings where HBV is endemic [60–62]. HBV vaccination is recom- mended for patients with end-stage renal and liver disease [20, 23]. Where unknown, HBV serology including the as- sessment of evidence of past or active infection (presence of HBs-antigen, anti-HBs and anti-HBc) must be assessed before any further steps including immunization. If there is evidence of past or active HBV infection, further evaluation (HBV-DNA, liver biopsy, indication for antiviral treatment) of the candidate in discussion with liver and infectious dis- eases specialists must be undertaken. In the HBV naïve SOT candidate or recipient the standard immunisation se- ries is to be used with 3 doses (see SIP) and anti HBs se- rology checked 1–3 months after completion. Since re- sponse to primary HBV vaccination may be impaired in pa-

tients with cirrhotic liver or chronic renal disease, it is par- ticularly important to start immunizations as early as possible in these patients if HBV vaccines were not admin- istered as part of routine immunizations [63]. As for most vaccines a poorer response has been described for patients post-transplant compared with the normal population [64, 65] with some evidence of the benefits of receiving pri- mary HBV immunisations prior to SOT with good response to boosters in this group [66].

Since there is a strong correlation between post-vaccina- tion titres and the protective effect of HBV immunisation, monitoring of anti-HBs serology post-immunisation is rec- ommended in SOT candidates and recipients. If 4 weeks after the primary course the anti-HBs titre is < 10 IU/l 3 ad- ditional doses should be administered. Thereafter if the ti- tre remains < 10 IU/l, administration of combined vaccine against Hepatitis A and Hepatitis B (Twinrix®) or high dose HBV vaccine (40ug HBs-antigen) can be tried and has vari- ably been reported to be more or less successful [67–73].

Monitoring of anti-HBs titres after primary immunization series, at pre-transplant evaluation and after transplantation is recommended with subsequent application of booster doses if the titre is < 10 IU/l [22, 66]. An anti-HBs titre > 100 IU/l should be documented 4 weeks after boostering.

HPVTransplant recipients with anogenital HPV infection are at 20–100-fold increased risk of cervical intraepithelial neopla- sia and other anogenital malignancies [74, 75]. At the pres- ent time, no published studies of immunogenicity of this vaccine in transplant recipients and candidates are yet available [76]. Since it is an inactivated vaccine, it could the- oretically be safely given after transplantation. For optimal response, it is however preferable to administer HPV vac- cine to SOT candidates before transplantation to girls aged

> 9 years. However, HPV vaccines are very immunogenic and should be considered for any transplant patient at risk of exposure. The use of HPV vaccine may also be consid- ered in boys > 9 years of age.

MenC disease

Transplant recipients may be given MenC conjugate vac- cine according to the SIP (1–5 years and 11–19 years). Im- munization against MenACWY is recommended to patients with splenic dysfunction or other risk factors [31] see in the section immunization for high risk subjects below.

Pneumococcal disease

Immunization against invasive pneumococcal disease with 13-valent pneumococcal conjugate vaccine should be con- sidered according to recommendations for the vaccination of less than 5-year-old children in the SIP. Immunization of groups at thigh risk for invasive pneumococcal disease in- cluding transplant candidates and recipients [77] see im- munization of high risk subjects below.

Immunizations for high risk subjects Influenza

Influenza infection in patients with chronic illness and SOT recipients is associated with increased morbidity and mor- tality, including severe pulmonary and extrapulmonary

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complications and may lead to decompensation [36, 78–

80]. Immunosuppressed patients with influenza infection have prolonged viral shedding [81, 82] and are at increased risk of allograft rejection [36, 83, 84]. In contrast, influenza immunization is not associated with a risk for development of allograft rejection after vaccination [33, 35, 36, 85, 86].

The influenza vaccine has been shown to be safe in SOT recipients, but to yield adequate antibody responses only in a part of SOT recipients [85, 87–89]. The specific immuno- suppressive regimen might contribute to the size of any impairment of the response to the vaccine [45, 90–93].

Given the limited immune response to influenza vaccina- tions in SOT recipients, approaches to increase the im- mune response have been tried using intradermal applica- tion [94–96] or using, for example, MF-59 adjuvanted vac- cine [97–102] with variable success.

Annual influenza vaccination is recommended for all pa- tients with progressive chronic organ disease likely to eventually result in SOT, SOT candidates and recipients, beginning 6 months after transplantation. Earlier vaccina- tion during the period of maximum immunosuppression during the first 6 months post-transplant has been shown to produce low antibody titres in recipients of kidney trans- plants [103]. To increase the immune response, SOT recipi- ents may be given a two-dose course of influenza immuni- zation instead of an annual single shot after individualized risk assessment, but current data do not allow for recom- mending an annual two dose schedule [18, 87, 104–108].

Invasive pneumococcal disease

Invasive pneumococcal infections can cause significant morbidity and mortality in SOT recipients [109]. Pneumo- cocccal vaccination is currently recommended in patients with chronic organ disease, including e.g. cardiovascular, renal, and liver disease (see SIP) [20, 23], as well as in SOT candidates and recipients [23]. As with other vaccines, pro- tective antibody titres are less reliably induced and known to decrease with time in patients with end-stage renal or end-stage liver disease and even more after SOT [110–112].

Thus vaccination is recommended to be given as early as indicated [77] in patients with chronic disease.

Available vaccines include the 13-valent conjugate vaccine (PCV13) and the 23-valent polysaccharide vaccine (PPSV23).

Vaccination for children < 1 year at risk includes PCV13 given as a four-dose series (2, 4, 6, and 12–15 months)[20].

Children < 5 years of age and immunocompromised chil- dren of any age who have been previously fully immunized with the PCV7 should receive one supplemental dose of PCV13. The data on immune responses to PCV (PCV7) in paediatric SOT recipients show that despite a response to initial vaccination, those to subsequent doses are lower and more transient than in healthy controls [113].

While the immune response in adult SOT recipients and other immunocompromised persons after one dose of ei- ther PPSV23 or PCV7 were similar after priming with PCV7 and boosting with PPSV23 [114, 115], another study in chil- dren showed impressively good responses in children given 2–3 doses of PCV7 only after > 1 year after transplan- tation [116]. The available data from SOT recipients and other immunocompromised persons, including in particular those with impaired T-cell function as in HIV infection or af- ter stem cell transplantation show increasing evidence for better efficacy and non-inferior immunogenicity of PCV in

comparison with PPSV [117–123]. Based on these findings, the short and limited effect of PPSV23, the risk for hypore- sponsiveness after repeated immunization with PPSV23 and the small difference in the coverage of the additional 10 serotypes only included in PPSV23 given the current epide- miology of invasive pneumococcal disease in Switzerland, PPSV23 is not recommended instead of or in addition to PCV13 in SOT candidates and recipients.

As PCV13-induced protection is also likely to be limited in time, one dose of PCV13 should be administered at listing and immunity boosted with a 2nd dose at 12 months after SOT. If a patient was not vaccinated with PCV13 before SOT, PCV13 catch-up should be given at 6 months post transplant. The booster dose at 12 months post-transplant, when immunosuppression is reduced, remains recom- mended regardless of the interval since the last dose.

PCV13 has been licensed by FDA and EMA (but not by Swissmedic) for immunocompromised persons with high risk for invasive pneumococcal infections and is recom- mended for such patients by the CDC/ACIP since 2012 [124]. Due to the lack of licensure of PCV13 use in adults by Swissmedic, this recommendation is off-label and may thus not be reimbursed by health insurances in Switzer- land.

Invasive meningococcal disease

Immunization against MenACWY should be recommended to all SOT candidates and recipients with splenic dysfunc- tion. The conjugate vaccine (Menveo®, Novartis vaccines) is more immunogenic and should be preferred to the polysac- charide vaccine (Mencevax®). Booster doses should be considered every 5 years , especially if there is an exposi- tion to mennigococi serogroup A [31].

Varicella

Varicella is known to cause severe disease especially in im- munocompromised hosts [125]. Despite the availability of a life-attenuated varicella zoster virus (VZV) vaccine (Varilrix®, Varivax®) with an efficacy of 70–90% against chickenpox and > 95% against severe disease in healthy hosts, VZV circulation is definitely persisting in the community, thus posing a risk for susceptible SOT recipients, children in par- ticular.

Live-attenuated VZV immunization in end-stage renal dis- eases and in SOT candidates is safe and effective [51, 126, 127]. As most adult transplant candidates are already im- mune to varicella, the disease history however is rarely documented. VZV serology (IgG) is thus recommended for all candidates. If VZV IgG is negative (Table 2) – and for children > 9 months of age without a history of chickenpox – immediate VZV vaccination (two doses one month apart) is highly recommended.

Varicella vaccination before transplantation is essential as, SOT candidates and recipients are a high-risk group, vac- cine responses are better before than after SOT, and the live attenuated VZV vaccine is officially contraindicated in immunocompromised patients. However, varicella vaccina- tion has been studied in paediatric SOT recipients and ac- cumulating evidence shows this vaccine to be safe and immunogenic in SOT recipients. While a vaccine response (protective antibody titre and cellular immunity) was seen in > 70% up to 100% of paediatric SOT recipients (kidney and liver), unwanted local and systemic effects including

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vaccine-induced varicella were mild and transient [18, 30, 57, 128–130]. Breakthrough disease was reported with a cumulative incidence of 0–25%, was mostly mild, rarely requiring hospital admission or antiviral treatment and oc- curred only in VZV antibody-negative SOT recipients [131].

Although these studies are and will remain underpowered to assess efficacy and severe adverse events, they allow considering varicella immunization in seronegative SOT re- cipients with minimal immunosuppression, the expected benefits (protection from varicella in countries where viral circulation is widespread) outweighing the theoretical risks of VZV vaccination (extensive viral replication, which could be controlled by antivirals).

Varicella vaccine is thus not only a first priority in suscepti- ble SOT candidates but also to be considered and recom- mended in stable VZV-seronegative SOT recipients with minimal immunosuppression if immunization before SOT did not occur and/or VZV immunity has waned.

Herpes zoster

Reactivation of VZV after primary infection, or herpes zoster infection, occurs with increased incidence in immunocom- promised hosts, including SOT recipients[132–134]. For pre- vention or mitigation of herpes zoster, a live attenuated zos- ter vaccine was developed. This vaccine is composed of the same viral strain (Oka) as the varicella vaccine but has a distinct (i.e.14-fold) higher virus titre. This vaccine should not be used in varicella naïve persons or person previously immunized with varicella vaccine. Despite the ACIP state- ment [135], it is currently neither available nor recom- mended in Switzerland – and clearly contraindicated after transplantation [136].

Hepatitis A

Hepatitis A virus (HAV) can cause severe disease and ful- minant hepatitis in patients with chronic viral hepatitis and in end-stage liver disease [137–140]. Vaccination against hepatitis A is thus recommended [20, 23] for patients with end-stage liver disease and may be considered in all SOT candidates at risks of exposure (travel) [28]. Antibody titres in response to hepatitis A vaccination are lower in patients with end-stage liver disease, and even more after SOT, compared to healthy subjects and may more rapidly de- crease after SOT [16, 65, 141–143]. If immunization is per- formed after SOT, HAV responses should thus be assessed 1–3 months after the second dose and a single HAV booster be administered to non-responders [22, 23, 143].

Other vaccinations (risk based assessment)

Every inactivated vaccine can be safely administered to SOT candidates and recipients. The potentially risks of poorer vaccine responses has to be taken into account, in particular in immunosuppressed SOT recipients. An indi- vidual discussion is strongly recommended to define the risk of exposure and discuss the possibility of providing protection against other vaccine-preventable disease. This may include vaccinations against TBE (FSME), hepatitis A, rabies, meningococcal disease or yellow fever (only be- fore SOT) when travel-associated exposure may be rele- vant.

In general, unless specifically indicated otherwise in this document, live vaccines are contraindicated after SOT.

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References